Hantavirus cardiopulmonary syndrome (HCPS) caused by Sin Nombre virus (SNV) is an often lethal condition for which there is no specific therapy. The brisk innate immune responses associated with exposure to the SNV particle may play a significant and as yet unappreciated role in the pathogenic process that leads to capillary leak and HCPS. The human innate immune system recognizes a variety of pathogen associated molecular patterns (PAMPs) (LPS, ssRNA, dsRNA, etc.) via pattern recognition receptors (PRR) including membrane bound Toll-like receptors (TLR) and cytoplasmic PRRs such as RIG-I and MDA-5. Hence the human immune response to viral infection can vary widely with different viruses, making it important to understand the scope of these response mechanisms. The innate immune response to viral RNA has been extensively studied, with less information available on the response to viral protein. We have chosen to focus on SNV not only because of the global health threat and because the potential use of SNV as a bio-weapon highlights the need to identify specific therapeutic targets for HCPS, but also because intervening in innate immune responses may offer therapeutic options against a variety of organisms with related pathogenic mechanisms. Towards this goal, there is a need to elucidate the mechanism(s) by which SNV infection triggers the innate immune system. Since viral RNA (vRNA) is severely damaged by UV exposure, we used UV-killed SNV to demonstrate that the innate immune response to SNV, as evidenced by induction of interferon-related genes ISG56 and MxA, occurs even in the absence of intact viral RNA. Accordingly, we propose that initial gene induction by UV-SNV is due to the host response to one or more components of the viral particle, rather than to a nucleic acid moiety, and is therefore independent of the conventional RNA recognition receptors, TLR3, TLR7/8, MDA-5 or RIG-I. The possibility that innate immune induction is driven, at least in part, by molecules exposed on the surface of the SNV virion, such as G1and/or G2 glycoproteins, provides a more readily accessible therapeutic target compared to membrane enclosed nucleic acid. Therefore, the specific aims of this project are 1) to examine the role of conventional innate immune receptors, including TLRs, RIG-I and MDA-5, in induction of the initial innate immune response to SNV, and 2) to examine the role of SNV glycoproteins G1/G2 in induction of the initial innate immune response to SNV. Together, the results from these experiments will identify the viral component(s) and host cell receptor(s) required for the pathogenic hantavirus SNV to trigger the innate immune response, and will be a crucial step towards identifying specific therapeutic targets to combat this pathogen. [unreadable] [unreadable] [unreadable]